Hemophilia A is a hereditary blood coagulation disorder caused by deficits of or mutations in Factor VIII (FVIII). Factor VIII is a crucial component in the intrinsic blood coagulation pathway. Deficiencies in Factor VIII cause increased bleeding. Hemophilia A is X linked and is observed in males at about 1 in 5000.
Hemophilia A patients are currently treated by intravenous administration of full length recombinant human FVIII. Treatment may be prophylactic or as necessitated in response to an injury causing bleeding. The half-life of Factor VIII in humans is relatively short, typically on the order of 11 hours. Hence, frequent dosages on the order of three times a week are required for effective treatment. However, such frequent dosing, typically via infusion, is undesirable, necessitating frequent visits to a clinic or other healthcare provider. Moreover, such frequent dosing may diminish patient compliance with prescribed dosing regimes.
Another drawback with current Factor VIII treatment is that some 25 to 30%, of Factor VII treated patients develop antibodies to FVIII. Patients with high levels of circulating anti-Factor VIII antibodies cannot be successfully treated with current Factor VIII therapeutics. Such patients require a more expensive treatment regime involving Factor VIIa and immune tolerance therapy.
The efficacy of a therapeutic agent may be enhanced by improving its bioavailability and pharmacokinetic properties. One approach to improving bioavailability has been PEGylation. PEGylation involves the addition of polyethylene glycol chains to a drug, typically a protein. A reduction in immunogenicity or antigenicity, increased half-life, increased solubility, decreased clearance by the kidney and decreased enzymatic degradation have been attributed to PEG conjugates. As a result of these attributes, it has been reported that PEG conjugates of certain biologically active agents sometimes require less frequent dosing and may permit the use of less of the active agent to achieve a therapeutic endpoint. Less frequent dosing is generally desirable because it reduces the overall number of injections, which can be painful and which require inconvenient visits to healthcare professionals.
Although some success has been achieved with PEG conjugation, “PEGylation” of biologically active agents remains a challenge. As drug developers progress beyond very potent agonistic proteins such as erythropoietin and the various interferons, potential benefits of the PEG hydrophilic polymer in increased solubility, stability and bioavailability do not sufficiently compensate for increased viscosity and immunogenicity.
PEGylation of FVIII has not been observed to significantly increase the half-life of the conjugate in vivo.
Thus there remains a need for FVIII drugs with increased in vivo half-life while retaining sufficient biological activity.